TWI397411B - Photodynamic cosmetic procedure and healing method - Google Patents

Photodynamic cosmetic procedure and healing method Download PDF

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TWI397411B
TWI397411B TW96101717A TW96101717A TWI397411B TW I397411 B TWI397411 B TW I397411B TW 96101717 A TW96101717 A TW 96101717A TW 96101717 A TW96101717 A TW 96101717A TW I397411 B TWI397411 B TW I397411B
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collagen
tissue
group
pdt
growth factors
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TW200803845A (en
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Volker Albrecht
Danilo Castro
Wolfgang Neuberger
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Biolitec Pharma Marketing Ltd
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    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract

Innovative non-surgical methods and compositions are provided for administering PDT to promote tissue regeneration or augmentation while minimizing scarring and risk of infection. Among several areas of application, is the treatment of acute and chronic wounds which have afflicted epidermal and connective tissue layers of the body. Another application area is as cosmetic surgery/treatments, including: reducing wrinkles, sulcus, scars (acne or traumatic caused), sequelae cellulite, as well as for other skin irregularities, to give a smoother skin surface. This invention consists of a collagen based or other suitable biodegradable supporting matrix which is embedded with a liposomal loaded photosensitizer. In one embodiment of this invention a liposomal formulated photosensitizer is first injected at the site followed by collagen implantation and PDT treatment. In another embodiment a liposomal formulated photosensitizer is incorporated in the collagen. Generally 30 minutes after collagen is mixed with photosensitizer the light activation is done. The matrix may also carry important growth factors and cytokines, which promote fibroblast cell migration and proliferation, to the wound site. Microbial infection at the wound site can also be controlled by antibacterial PDT.

Description

光動力美容步驟及癒合方法Photodynamic beauty step and healing method 發明背景Background of the invention

1.35 USC 119(e)下之優先權本專利申請案要求2006年1月18日所提交之第60/759,660號美國臨時專利申請案的利益，其係由Volker Albrecht，Danilo Castro及Wolfgang Neuberger命名為”光動力美容步驟及癒合方法”，其在此以參考方式納入本文中。1.35 USC 119(e) priority This patent application claims the benefit of U.S. Provisional Patent Application Serial No. 60/759,660, filed on Jan. 18, 2006, which is assigned by Volker Albrecht, Danilo Castro and Wolfgang Neuberger "Photodynamic cosmetic steps and healing methods", which are incorporated herein by reference.

2.【發明所屬之技術領域】一般而言，本發明係關於用於傷口癒合及美容應用之光動力療法，特別係會加強損傷的表皮及結締組織傷口之癒合過程，因而促進組織重建與增大的方法及組成物。2. Technical Field of the Invention In general, the present invention relates to photodynamic therapy for wound healing and cosmetic applications, in particular, to strengthen the healing process of damaged epidermal and connective tissue wounds, thereby promoting tissue reconstruction and growth. Large methods and compositions.

3.資訊揭露聲明書傷口係皮膚組織完整性的瓦解，造成該區域功能喪失。傷口可以是簡單的，像是輕微的切口或擦傷，其牽涉到表皮及表面真皮層及被稱為部分－厚度傷口。此藉由上皮再形成而癒合較快速；而複雜/完全厚度傷口係較深層的損傷於骨骼系統、肌肉組織或甚至於內部器官。傷口可以是創傷性傷口，像是擦傷、挫傷、撕裂傷；或外科手術性傷口－皮膚移植、外科手術後刀口，其係最容易癒合；或它們可以是慢性/非癒合性傷口，像是褥瘡或糖尿病潰瘍，其係癒合較困難。損傷於結締組織，像是骨骼、軟骨也係非常常見。最後，燒傷性損傷，特別是第二及第三級，其中組織損失造成疤痕及毀容，且延遲癒合過程，也係主要關注事項。3. Information Disclosure Statement Wounds are the breakdown of skin tissue integrity, resulting in loss of function in the area. The wound can be simple, like a slight incision or abrasion, involving the epidermis and the surface dermis and is referred to as a partial-thickness wound. This is healed faster by epithelial re-formation; while complex/complete thickness wounds are more deeply damaged by the skeletal system, muscle tissue or even internal organs. The wound can be a traumatic wound, such as a bruise, a contusion, a laceration; or a surgical wound-skin graft, a knife edge after surgery, which is most likely to heal; or they can be chronic/non-healing wounds, like Hemorrhoids or diabetic ulcers are more difficult to heal. Damage to connective tissue, such as bones and cartilage, is also very common. Finally, burn injuries, especially in the second and third grades, where tissue loss causes scarring and disfigurement, and delays the healing process are also major concerns.

傷口癒合係一種牽涉生理、生化及型態改變之動態過程。損傷後修復及重建的過程係對抗環境最基本的防禦機制之一。此癒合過程係由有次序之連續事件所組成，其重新建立受傷害組織之完整性。它包括單獨但重疊之階段，那就是－止血、發炎、增生、血管新生及重塑，其係藉由基質與必須細胞之累積用以癒合受損傷部分。所有健康活體具有天賦能力用以癒合傷口。但是在某些個案中，傷口可能不容易癒合或由於減弱的免疫力、虛弱的健康狀況，及/或營養缺乏而有所延緩；舉例而言，在糖尿病患者中，傷口癒合係減弱的及即使是簡單的切口會出現慢性傷口(假如沒有提供立即醫療照護)。新式技術正被建立用以在這些狀況中改善癒合。Wound healing is a dynamic process involving physiological, biochemical, and morphological changes. The process of repair and reconstruction after injury is one of the most basic defense mechanisms against the environment. This healing process consists of sequential sequential events that re-establish the integrity of the injured tissue. It consists of separate but overlapping stages, namely - hemostasis, inflammation, hyperplasia, angiogenesis and remodeling, which are used to heal the damaged part by the accumulation of matrix and essential cells. All healthy living bodies have the natural ability to heal wounds. However, in some cases, the wound may not be easily healed or may be delayed due to weakened immunity, debilitating health, and/or nutritional deficiencies; for example, in diabetic patients, wound healing is weakened and even A simple incision can result in a chronic wound (if no immediate medical care is provided). New technologies are being developed to improve healing in these conditions.

傷口癒合係複雜之過程，其牽涉許多不同的細胞、蛋白質、趨化因子、蛋白酵素、發炎細胞、細胞介素及生長因子。癒合過程係藉由生長因子及細胞介素被調控，其影響細胞遷移、增生及蛋白質製造。就在受損傷之後，傷口會充滿血液及凝集被形成以止血。假如組織受到傷害，一連串細胞事件被啟動，用以使受損傷區域準備堆積膠原蛋白，其最終將取代受傷害之組織。在發炎階段期間，出血係受到控制及免疫系統係被活化用以控制細菌感染；及肉芽組織係在增生階段期間被形成，其覆蓋受損傷之區域。在此之後為血管新生及重塑。Wound healing is a complex process involving many different cells, proteins, chemokines, proteolytic enzymes, inflammatory cells, interleukins, and growth factors. The healing process is regulated by growth factors and interleukins that affect cell migration, proliferation, and protein production. Immediately after the injury, the wound is filled with blood and agglutination is formed to stop bleeding. If the tissue is damaged, a series of cellular events are initiated to prepare the damaged area for collagen accumulation, which will eventually replace the damaged tissue. During the inflammatory phase, the bleeding system is controlled and the immune system is activated to control bacterial infection; and the granulation tissue is formed during the proliferative phase, which covers the damaged area. This is followed by angiogenesis and remodeling.

瞭解細胞介素、生長因子及其他牽涉於傷口癒合過程之媒介者的功能，能幫助我們操縱這些成分，用以快速地治癒傷口，因而改善功能及美感。最廣泛地被實行之局部性傷口處理的傳統方法係由以下所組成：機械式洗淨、以殺菌溶液消毒、傷口清創、傷口閉合、抗生素處理，及藉由外科手術方法進行傷口閉合。Understanding the functions of interleukins, growth factors, and other mediators involved in the wound healing process can help us manipulate these components to quickly heal wounds, thereby improving function and aesthetics. The most widely practiced traditional method of topical wound treatment consists of mechanical washing, disinfection with sterilizing solution, wound debridement, wound closure, antibiotic treatment, and wound closure by surgical procedures.

傷口癒合係由三種機制之組合被控制：孿縮、上皮細胞增生及結締組織堆積。傷口形式(即擦傷、撕裂傷等)將決定這三種機制之中哪一種會在癒合過程顯現成為主要機制。舉例而言，擦傷之癒合係藉由上皮細胞增生主導，然而對於縫合的撕裂傷，首要機制係結締組織堆積。藉由外科手術方法來閉合傷口仍舊係促進傷口癒合之最佳方式，然而，並非所有傷口均適合外科手術介入。解剖上之位置以及傷口之表面區域及/或深度可使傷口閉合之外科手術方法不可能或不可行。更進一步，組織移除及一些外科手術方法後之疤痕可以是高度毀容及令人衰弱的。皮膚孿縮的結果造成大規模的傷口(例如燒傷)限制肢體移動或功能，其係由於在傷口部位之皮膚或結締組織中，疤痕組織之皺縮。Wound healing is controlled by a combination of three mechanisms: contracture, epithelial cell proliferation, and connective tissue accumulation. The form of the wound (ie, abrasion, laceration, etc.) will determine which of these three mechanisms will appear as the primary mechanism in the healing process. For example, healing of the abrasion is dominated by epithelial cell proliferation, whereas for sutured lacerations, the primary mechanism is connective tissue accumulation. Closed wounds by surgical procedures are still the best way to promote wound healing, however, not all wounds are suitable for surgical intervention. The anatomical location and the surface area and/or depth of the wound may make it impossible or impossible for the wound to be closed. Further, scar removal after tissue removal and some surgical procedures can be highly disfiguring and debilitating. As a result of skin contracture, large-scale wounds (such as burns) limit limb movement or function due to shrinkage of scar tissue in the skin or connective tissue of the wound site.

最新處理方法係使用組織工程化之”皮膚替代物”。其中科學家已經建立使用包埋於生物可分解基質中之纖維母細胞片，培養之角質細胞片及雙層真皮/表皮工程化之皮膚的移植物。一種該例子係使用Integra人造皮膚(Burke及Yannas在1980年代所建立)。Yannas等人在他的美國專利號碼4,947,840中揭示使用此生物可分解之人造皮膚移植物，其用於在具有組織缺失之燒傷傷口中，延緩孿縮及促進組織再生。Integra DRT只能取代較深的真皮皮膚層，及仍需要皮膚移植物用以覆蓋它及防止感染。The latest treatment method uses tissue engineered "skin substitutes." Among them, scientists have established grafts of fibroblasts embedded in biodegradable matrices, cultured keratinocytes and double-layered dermis/skin-engineered skin. One such example uses Integra artificial skin (established by Burke and Yannas in the 1980s). The use of this biodegradable artificial skin graft for delaying contracture and promoting tissue regeneration in burn wounds with tissue loss is disclosed in U.S. Patent No. 4,947,840. Integra DRT can only replace the deeper dermal skin layer and still require a skin graft to cover it and prevent infection.

很多該產品已經被FDA所核准(例子：Integra DRT、TransCyte)。Integra真皮再生模版(Integra Dermal Regeneration Template)係無細胞之基質，其包括鍍於薄矽膠片之多孔性膠原蛋白/chondritein－6硫酸鹽基質。此模版係作用當作骨架用於真皮再生，因而抑制疤痕及促進癒合。像無細胞基質一樣，含細胞基質係也被用於格柵；例子為Dermagraft、Apligraf，及Hyalograft－3D等。即使是由於疾病之骨骼及軟骨組織的破壞，及創傷損傷後無效率之骨骼癒合，也可能藉由組織工程技術而被對付。但是組織工程化之皮膚移植物在較大規模製造上係昂貴及有期限的。有時候此種皮膚移植物顯現差勁的接收速率，及在移植到患者上時常常失敗。Many of these products have been approved by the FDA (examples: Integra DRT, TransCyte). The Integra Dermal Regeneration Template is a cell-free matrix comprising a porous collagen/chondritein-6 sulfate substrate plated on a thin film. This stencil acts as a skeleton for dermal regeneration, thereby inhibiting scarring and promoting healing. Like cell-free matrices, cell-containing matrix systems are also used for grids; examples are Dermagraft, Apligraf, and Hyalograft-3D. Even the destruction of bones and cartilage tissue of the disease and the ineffective bone healing after traumatic injury may be countered by tissue engineering techniques. However, tissue engineered skin grafts are expensive and time consuming in larger scale manufacturing. Sometimes such skin grafts exhibit poor rate of reception and often fail when transplanted to a patient.

最近，在光線對於傷口癒合之效果上已經有顯著的興趣。某些雷射已經被證明係加速癒合過程之有效、非侵入性的方法。舉例而言，使用高功率980nm雷射用以加速傷口癒合係被Neuberger描述於美國專利號碼6,165,205中。因此，經雷射幫助傷口癒合對於外科手術方法而言會是一種吸引人的替代方案。光動力療法(”PDT”)係另一種雷射處理方法，其使用特定波長照射用以活化光敏藥物。藥物之光活化誘使區域性氧化傷害於生病組織(其中光敏物已經優先地累積)。PDT係被認為在傷口癒合過程上同樣具有正面效果。Recently, there has been a significant interest in the effect of light on wound healing. Certain lasers have proven to be an effective, non-invasive method of accelerating the healing process. For example, the use of high power 980 nm lasers to accelerate wound healing is described by Neuberger in U.S. Patent No. 6,165,205. Therefore, laser assisted wound healing can be an attractive alternative to surgical methods. Photodynamic therapy ("PDT") is another laser processing method that uses specific wavelength illumination to activate a photosensitizing drug. Photoactivation of the drug induces regional oxidative damage to the diseased tissue (where the photosensitizer has preferentially accumulated). The PDT system is believed to have a positive effect on the wound healing process as well.

由於在傷口癒合領域中持續的研究，已發現光療法可以改善組織癒合。低功率雷射能量已經被使用於傷口癒合，因為它可以明顯地引起細胞反應，因而促進癒合過程。Neuberger之美國專利號碼6,165,205中，討論使用高功率非剝離性雷射用以加速傷口癒合。980nm二極體雷射在此被利用以在傷口部位活化纖維母細胞及膠原蛋白合成，用以促進傷口癒合。而在同一發明人之美國專利號碼6,527,764中，一種裝置被描述用於雷射處理，其結合活化雷射功率與生物調節功率以在處理後加強組織癒合及再生。Due to ongoing research in the field of wound healing, light therapy has been found to improve tissue healing. Low-power laser energy has been used for wound healing because it can significantly cause cellular responses, thereby promoting the healing process. The use of high power non-peelable lasers to accelerate wound healing is discussed in U.S. Patent No. 6,165,205 to Neuberger. A 980 nm diode laser is utilized here to activate fibroblasts and collagen synthesis at the wound site to promote wound healing. In the same inventor's U.S. Patent No. 6,527,764, a device is described for use in laser processing in combination with activating laser power and biologically regulated power to enhance tissue healing and regeneration after treatment.

在最近十年中低能量光源已經被用於處理許多組織中之傷口或損害。低能量雷射(特別是He－Ne雷射)已經被發現用以促進完全厚度傷口中之上皮化。事實上，NASA已經建立一種手握式LED，其大大地加強傷口癒合及骨骼肌肉損傷。LED及低能量雷射療法已經被發現在試管內用以增加纖維母細胞增生(Vinck等人)。使用來自可見、近紅外、近紫外(UVA)光之低功率光源已經顯示在促進細胞增生與生長係有效果的，而高能量光可以抑制細胞生長。Low energy sources have been used to treat wounds or lesions in many tissues in the last decade. Low energy lasers (especially He-Ne lasers) have been found to promote epithelialization in full thickness wounds. In fact, NASA has established a hand-held LED that greatly enhances wound healing and skeletal muscle damage. LED and low-energy laser therapy have been found in vitro to increase fibroblast proliferation (Vinck et al.). The use of low power sources from visible, near infrared, near ultraviolet (UVA) light has been shown to be effective in promoting cell proliferation and growth, while high energy light can inhibit cell growth.

舉例而言，用於在未癒合或部分癒合之傷口中調控癒合過程的PDT方法已經被Trauner等人描述於美國專利號碼5,913,884中。Trauner等人揭示及請求一種高劑量PDT方法，其用於在癒合過程期間，抑制纖維化，膠原蛋白密集帶之快速製造。Trauner描述一種三步驟過程，其牽涉在給予與特異於巨噬細胞或肌纖維母細胞之標靶部分共軛鍵結之光敏物後，傷口部位之光照射。For example, a PDT method for modulating a healing process in a wound that has not healed or partially healed has been described by Trauner et al. in U.S. Patent No. 5,913,884. Trauner et al. disclose and request a high dose PDT method for inhibiting fibrosis and rapid manufacturing of collagen dense bands during the healing process. Trauner describes a three-step process involving light irradiation of a wound site after administration of a photosensitizer that is conjugated to a target portion specific to macrophages or myofibroblasts.

Hasan等人在美國專利號碼6,107,466中揭示用於加速傷口癒合之低劑量PDT方法。Hasan之PDT方法需要三步驟過程，其牽涉在給予光敏物之後傷口部位的光照射，及係意欲用以刺激生長因子之分泌於傷口部位細胞中。此外，Hasan等人請求加速傷口癒合而無造成組織破壞之PDT方法。A low dose PDT method for accelerating wound healing is disclosed in U.S. Patent No. 6,107,466 to Hasan et al. Hasan's PDT method requires a three-step process involving light irradiation at the wound site after administration of the photosensitizer, and is intended to stimulate secretion of growth factors in the cells of the wound site. In addition, Hasan et al. requested a PDT method that accelerates wound healing without causing tissue damage.

PDT係使用於治療某些癌症形式之新式治療療法，然而PDT之使用於癒合及疤痕移除中係處於熱烈的研究下，但未完全地被探究。抗細菌生長於傷口部位中需要被控制以促進癒合。紫外光(UVA)已經被報導用以殺死此細菌細胞。而在PDT處理方法中，PS可以被連接以專一標靶細菌細胞，如此使得光活化反應將會破壞細菌細胞。PDT is used in new therapeutic therapies for the treatment of certain forms of cancer. However, the use of PDT in healing and scar removal is under intense research but has not been fully explored. Anti-bacterial growth in the wound site needs to be controlled to promote healing. Ultraviolet light (UVA) has been reported to kill this bacterial cell. In the PDT treatment method, PS can be ligated to specifically target bacterial cells such that the photoactivation reaction will destroy the bacterial cells.

使用PDT於傷口癒合過程中已經分別被Hasan等人與Trauner等人報導於美國專利號碼6,107,466及5,913,884中。專利6,107,466描述在未癒合及部分癒合傷口中，用於加速癒合過程之PDT處理方法。在本專利中，有效之PDT劑量被選擇用以刺激生長因子之製造，而不傷害細胞，以在傷口部位促進癒合。Trauner等人在他們的專利(5,913,884)中描述三步驟PDT方法，用以處理未癒合及部分癒合傷口，其係藉由使用高劑量PDT抑制纖維化，抑或透過低劑量PDT加快癒合過程。The use of PDT in the wound healing process has been reported by Hasan et al. and Trauner et al. in U.S. Patent Nos. 6,107,466 and 5,913,884, respectively. Patent 6,107,466 describes a PDT treatment method for accelerating the healing process in non-healing and partially healing wounds. In this patent, an effective PDT dose is selected to stimulate the manufacture of growth factors without damaging the cells to promote healing at the wound site. Trauner et al., in their patent (5,913,884), describe a three-step PDT method for treating non-healing and partially healing wounds by inhibiting fibrosis with high doses of PDT or by slowing the healing process with low doses of PDT.

雖然這些參考文獻討論PDT與傷口癒合之關聯，但他們之中沒有任何一個描述或揭示如何或為何PDT方法(對於其中組織增大或置換係關鍵因子於所伴隨之傷口癒合的個案中)係有利的或能夠被使用。除那個之外，有很多例子，其中對於”無傷口”、健康的組織，有時候藉由組織增大或置換來加強”健康組織”係特別所欲的。Although these references discuss the association of PDT with wound healing, none of them describes or reveals how or why the PDT method (for cases where tissue enlargement or replacement factor is involved in the accompanying wound healing) is beneficial. Or can be used. In addition to that, there are many examples in which for "no wounds", healthy tissues, sometimes "health organizations" are particularly desirable by tissue enlargement or replacement.

於是，對於可信賴及可行的組織修復與傷口閉合的方法(其係適合用於完全或部分厚度傷口，例如燒傷或慢性潰瘍)有迫切的需要。對於其中組織增大或置換為必須之傷口，促進或加速癒合過程而最低化疤痕及感染風險之非外科手術療法係高度所欲的。本發明滿足這個需要。Thus, there is an urgent need for a reliable and viable tissue repair and wound closure method that is suitable for use in complete or partial thickness wounds, such as burns or chronic ulcers. Non-surgical therapies that minimize or minimize the risk of scarring and infection are highly desirable for wounds where tissue enlargement or replacement is necessary. The present invention satisfies this need.

本發明目標在於克服以上所討論之目前使用於癒合複雜傷口處理程序的缺點。本發明提供基於最低限度地侵入性、非外科手術PDT之處理方法，其促進傷口癒合及最低化疤痕。此外，本發明係不僅用於所有部分及完全厚度傷口形式，而且也用以降低疤痕、皺紋及其他皮膚瑕疵或美容情況。It is an object of the present invention to overcome the shortcomings discussed above for healing complex wound treatment procedures. The present invention provides a treatment method based on minimally invasive, non-surgical PDT that promotes wound healing and minimizes scarring. In addition, the present invention is not only useful for all partial and full thickness wound forms, but also for reducing scarring, wrinkles, and other skin blemishes or cosmetic conditions.

發明之目的及概要Purpose and summary of the invention

本發明之一個目的係提供用於傷口癒合之組成物及PDT方法，其係藉由組織置換或增大來降低癒合時間及最低化疤痕形成。It is an object of the present invention to provide a composition for wound healing and a PDT method which reduces healing time and minimizes scar formation by tissue replacement or enlargement.

本發明之另一目的係提供用以啟動細胞增生及/或傷口重建之組織基質，其係膠原蛋白或在其他基於生物可分解之支撐組織。Another object of the invention is to provide a tissue matrix for initiating cell proliferation and/or wound remodeling, which is collagen or other biodegradable support tissue.

本發明之另一目的係使用雷射/非雷射光源用於癒合傷口(在後PDT處理時程之期間)。Another object of the invention is to use a laser/non-laser source for healing wounds (during the post-PDT treatment schedule).

幫助經使用膠原蛋白基質PDT處理之癌症傷口的較快速癒合係本發明之目標。Helping the faster healing of cancer wounds treated with collagen matrix PDT is the object of the present invention.

使用膠原蛋白基質及PDT於美容用途也係本發明之另一目標，例如減少皺紋、細紋、疤痕(痤瘡或外傷性的)及其他皮膚瑕疵。The use of a collagen matrix and PDT for cosmetic purposes is also another object of the invention, such as reducing wrinkles, fine lines, scars (acne or traumatic) and other skin imperfections.

提供網羅於組織基質、裝載於微脂粒之PS(其共軛連結到生物分子以標靶特定細胞)也係本發明之目的。提供傷口癒合之非外科手術方法依然係本發明之另一目的。It is also an object of the invention to provide a PS that is networked on a tissue matrix and loaded on a liposome (which is conjugated to a biomolecule to target a particular cell). A non-surgical method of providing wound healing remains another object of the present invention.

提供組成物及方法用以在癒合及恢復期間防止細菌生長於傷口部位仍係本發明之另一目的。It is still another object of the invention to provide compositions and methods for preventing bacterial growth in the wound site during healing and recovery.

灌注生長因子、細胞介素及其他對於組織癒合所需之細胞成分到組織基質係更進一步的目的。Infusion of growth factors, interleukins, and other cellular components required for tissue healing to the tissue matrix further.

簡短地描述，本發明提供創新、非外科手術方法及組成物，其用於給予PDT以促進組織再生或增大，而最低化疤痕及感染風險。在幾種應用領域之一係急性及慢性傷口(其已經侵犯到身體之上皮及結締組織層)之處理。另一應用領域係當作美容外科手術/處理，包括：降低皺紋、溝、疤痕(痤瘡或創傷所造成)、橘皮組織後遺症，以及用於其它皮膚異常，以給予較平滑的皮膚表面。本發明係由基於膠原蛋白或其他適合的生物可分解支撐基質(其係包埋有裝載於微脂粒之光敏物)所組成。在本發明之一個具體實例中，微脂粒調配之光敏物係首先被注射到該部位，接著膠原蛋白移植及PDT處理。在另一個具體實例中，微脂粒調配之光敏物係被納入膠原蛋白中。一般而言，在膠原蛋白與光敏物混合30分鐘後，完成光活化。基質也可以攜帶重要的生長因子及細胞介素，其促進纖維母細胞遷移及增生於傷口部位。在傷口部位的微生物感染也能夠透過抗菌PDT控制。Briefly described, the present invention provides innovative, non-surgical methods and compositions for administering PDT to promote tissue regeneration or augmentation while minimizing scar and infection risk. One of several areas of application is the treatment of acute and chronic wounds that have invaded the epithelium and connective tissue layers of the body. Another area of application is cosmetic surgery/treatment, including: reducing wrinkles, sulcus, scars (caused by acne or trauma), cellulite sequelae, and other skin abnormalities to give a smoother skin surface. The present invention consists of collagen-based or other suitable biodegradable support matrix embedded in a light-sensitive film loaded with vesicles. In one embodiment of the invention, the light-fat-modulated photosensitizer is first injected into the site, followed by collagen transplantation and PDT treatment. In another embodiment, the liposome-modulated photosensitizer is incorporated into the collagen. In general, photoactivation is accomplished after collagen is mixed with the photosensitizer for 30 minutes. The matrix can also carry important growth factors and interleukins that promote fibroblast migration and proliferation in the wound site. Microbial infections at the wound site can also be controlled by antibacterial PDT.

本發明之以上及其他的目的、特徵及優點將從以下描述，並與所伴隨之圖式共同被閱讀而變的顯而易見。The above and other objects, features, and advantages of the present invention will be apparent from the description and accompanying drawings.

較佳具體實例之詳細說明Detailed description of preferred embodiments

傷口係在身體任何部位之組織構造及其功能的破壞。而癒合係該等構造及功能之復原，且它是連續之複合有相互關係的過程，其牽涉不同形式的細胞、生長因子、細胞外基質等。在某些傷口癒合過程受損的個案中，造成未癒合傷口。對於延遲或未癒合傷口的理由可以是受損的傷口癒合過程、患者之健康及營養狀況、年齡、供應於傷口部位之氧氣等。The wound is tied to the tissue structure and function of any part of the body. Healing is the restoration of these structures and functions, and it is a continuous process of interrelationship involving different forms of cells, growth factors, extracellular matrices, and the like. In some cases where the wound healing process is impaired, an unhealed wound is caused. The reasons for the delayed or non-healing wound may be the damaged wound healing process, the health and nutritional status of the patient, the age, the oxygen supplied to the wound site, and the like.

在過去的幾個十年中，很多不同種類的療法已經被建立，用以促進較快速的傷口癒合。最新係組織工程化”皮膚移植”、低水平光療法及光動力療法(PDT)。使用光源之光動力療法(PDT)已經顯示加強傷口修復。In the past few decades, many different types of therapies have been established to promote faster wound healing. The latest is tissue engineered "skin grafting", low-level phototherapy and photodynamic therapy (PDT). Photodynamic therapy (PDT) using light sources has been shown to enhance wound healing.

本發明係提供適合的PDT方法及基於膠原蛋白或生物之支撐基質，其包埋有適合地調配之光敏物(微脂粒、聚乙二醇化(Pegylation)等)，用以改善癒合過程。此方法可以被應用以有效地處理燒傷，用以修復在膝蓋中受傷害的軟骨表面及修復血管傷害、血管靜脈及動脈潰瘍、失效的縫合處或二次瘢痕增生之表面及用以降低皮膚瑕疵，像是疤痕、皺紋及其他美容情況。The present invention provides a suitable PDT method and a collagen or bio-based support matrix embedded with a suitably formulated photosensitizer (lipid, PEGylation, etc.) to improve the healing process. This method can be applied to effectively treat burns to repair damaged cartilage surfaces in the knee and repair vascular injuries, vascular and arterial ulcers, failed sutures or secondary scar hyperplasia surfaces and to reduce skin blemishes. Like scars, wrinkles and other cosmetic conditions.

所使用的術語膠原蛋白包括Auto、Allo、合成及半合成膠原蛋白的例子(其包括Chondro－Gide、Chondrocell、Bio－Gide、Gentacoll、Kollagen Resorb(Resorba GmbH)及Collagen Fibrils(Collagen Matrix公司)Kollagen Resorb)。此膠原蛋白係基於被處理之傷害的形式被使用。The term collagen used includes examples of Auto, Allo, synthetic and semi-synthetic collagen (including Chondro-Gide) Chondrocell Bio-Gide , Gentacoll, Kollagen Resorb (Resorba GmbH) and Collagen Fibrils (Collagen Matrix) Kollagen Resorb). This collagen is used based on the form of the damage being treated.

名詞光敏物(如此中所使用)包括光敏劑、光敏傳遞系統，及光敏物衍生物(來自母結構或選自由以下所組成群組之前驅藥物：紫質、紫質元、血紫質、去鎂葉綠素酸、二氫卟酚、菌綠素、異－菌綠素及二氫－及四氫－四吡咯)。The term photoactive material (used herein) includes a photosensitizer, a photoactive delivery system, and a photodeceptor derivative (from a parent structure or a drug selected from the group consisting of: purple, purple, blood, purple, Magnesium chlorophyll, chlorin, bacteriochlorin, iso-bacteriochlorin and dihydro- and tetrahydro-tetrapyrrole.

在本發明之一個具體實例中，基於膠原蛋白或其他生物可分解之支撐組織基質係被置於傷口部位或被注射到皮膚之下。此支撐基質具有相似於自然人類皮膚的真皮成分。光敏物(PS)被裝載到微脂粒中，以確保在該部位受到控制的藥物傳遞，此裝載PS之微脂粒係被灌注到組織基質中。除此之外，組織基質也由重要的生長因子(像是表皮生長因子、血小板衍生的生長因子、組織血管新生生長因子及細胞介素)、角質細胞及纖維母細胞所組成，用以加速癒合過程。GF及細胞介素控制關鍵細胞活性，包括細胞***、分化及組織修復。In one embodiment of the invention, collagen or other biodegradable support tissue matrix is placed at the wound site or injected under the skin. This support matrix has a dermal component similar to natural human skin. The photosensitizer (PS) is loaded into the liposome to ensure controlled drug delivery at the site, and the PS-loaded vesicles are infused into the tissue matrix. In addition, the tissue matrix is composed of important growth factors (such as epidermal growth factor, platelet-derived growth factor, tissue angiogenic growth factor and interleukin), keratinocytes and fibroblasts to accelerate healing. process. GF and interleukin control key cell activities, including cell division, differentiation, and tissue repair.

在本發明中，不同形式之膠原蛋白海綿(像是Gentacoll、Kollagen Resorb(Resorba GmbH)及Collagen Fibrils(Collagen Matrix公司))係與PDT被使用於癒合不同形式之傷口及用以改善皮膚表面之美容外觀。在臉及頸部區域上皺紋減少的個案中，需要可注射的膠原蛋白調配物以用於最佳的美容效果。透過細針，膠原蛋白被注射到正好在皮膚表面之下，以撫平皺紋。可注射膠原蛋白之例子係Zyplast及Zyderm(美國Inamed Aesthetics公司所製造)。Zyplast及Zyderm係衍生自牛皮之膠原蛋白。In the present invention, different forms of collagen sponges (such as Gentacoll, Kollagen Resorb (Resorba GmbH) and Collagen Fibrils (Collagen Matrix)) and PDT are used to heal different forms of wounds and to improve the appearance of the skin surface. Exterior. In cases where wrinkles are reduced on the face and neck area, injectable collagen formulations are needed for optimal cosmetic results. Through the fine needle, collagen is injected just below the surface of the skin to smooth out wrinkles. Examples of injectable collagen are Zyplast and Zyderm (manufactured by Inamed Aesthetics, USA). Zyplast and Zyderm are derived from the collagen of cowhide.

此外，許多Hyaluronic acid(一種非動物性穩定型透明質酸)也可以被使用，如同以上膠原蛋白被使用以矯正皺紋、疤痕及其他皮膚畸形，以用於美學目的。透明質酸係天然發現於人體中的物質。它在自然界中係親水性，因此當其使用作填充物時，作用當作海綿以吸收水分及提供長時間、持續的結果，而具過敏反應低風險。In addition, many Hyaluronic acids (a non-animal stable hyaluronic acid) can be used as above to correct wrinkles, scars and other skin deformities for aesthetic purposes. Hyaluronic acid is a substance naturally found in the human body. It is hydrophilic in nature, so when used as a filler, it acts as a sponge to absorb moisture and provide long-lasting, sustained results with a low risk of allergic reactions.

圖2及3給定在膠原蛋白及具有裝載於微脂粒之mTHPC的膠原蛋白中，當曝露於不同能量水平時，熱穩定性之巨觀及微觀圖片。Figures 2 and 3 show macroscopic and microscopic images of thermal stability when exposed to collagen and proteins in mTHPC loaded with vesicles when exposed to different energy levels.

膠原蛋白穩定性係在一能量水平範圍(0到200J/cm2 )內被測試，圖2及3闡明在不同能量水平下，膠原蛋白穩定性之試管內實驗結果。在實驗中可注意膠原蛋白結構在高光線劑量係未改變。因此可證明即使在較高光線劑量，該膠原蛋白材料可以被使用而不會影響/傷害膠原蛋白結構。Collagen stability was tested in an energy level range (0 to 200 J/cm 2 ). Figures 2 and 3 illustrate the results of in vitro experiments with collagen stability at different energy levels. It is noted in the experiments that the collagen structure is unchanged in the high light dose system. It can therefore be demonstrated that even at higher light doses, the collagen material can be used without affecting/damaging the collagen structure.

Zyplast及Zyderm已經被使用以移除皺紋、疤痕、深紋及其他皮膚異常，但它們的效果只持續3－6個月期間。在本發明中，膠原蛋白基質係結合PDT被使用，以改善美容效果還有它們的耐久性。PDT刺激該區域天然的膠原蛋白製造細胞，及達成所移植之膠原蛋白納入皮膚之膠原蛋白的事實，它本身解釋了它的較大耐久性。Zyplast and Zyderm have been used to remove wrinkles, scars, deep lines and other skin abnormalities, but their effects last only for 3-6 months. In the present invention, a collagen matrix is used in combination with PDT to improve cosmetic effects as well as their durability. The fact that PDT stimulates the region's natural collagen-producing cells and the collagen that the transplanted collagen incorporates into the skin itself explains its greater durability.

在一個具體實例中，本發明係使用於皮膚更新及用於美容理由，其包括矯正輪廓畸形、皺紋降低、痤瘡疤痕、凹洞、外科手術引起之異常及其他軟－組織缺損。因為老化，真皮會隨時間喪失膠原蛋白及彈性蛋白，因為此原因皮膚變的較薄及不平坦而造成皺紋。皺紋可以只是皮膚上的細紋或深紋。其他促進皺紋的原因係抽煙、陽光傷害(光老化)、乾燥及濕度缺乏、膚色(淺色皮膚係較易於發展出皺紋)，及遺傳等。In one embodiment, the invention is used for skin renewal and for cosmetic reasons including correcting contour deformities, wrinkle reduction, acne scars, cavities, surgically induced abnormalities, and other soft-tissue defects. Because of aging, the dermis loses collagen and elastin over time, because for this reason the skin becomes thinner and uneven and causes wrinkles. Wrinkles can be just fine lines or deep lines on the skin. Other causes of wrinkles are smoking, sun damage (photoaging), lack of dryness and humidity, skin color (light skin is more likely to develop wrinkles), and genetics.

在本發明之進一步具體實例中，雷射/非雷射光源係與PDT及膠原蛋白基質被使用。在給予PDT及膠原蛋白於傷口部位後，980nm雷射光被用於生物刺激該處理區域，以用於加快癒合及降低疤痕形成。當被直接應用在皮下細胞組織，使用200μ具低功率及高發射期之光纖時，雷射光980也被使用於首先填滿水腫及之後增加膠原蛋白基質，除此之外，980 nm與具微貸點(micro lent point)之纖維的外部使用也在它們的第一階段中降低每目鏡皺紋紋路。In a further embodiment of the invention, a laser/non-laser source is used with the PDT and collagen matrix. After administration of PDT and collagen to the wound site, 980 nm laser light was used to biostimulate the treatment area for accelerated healing and reduced scar formation. When applied directly to subcutaneous tissue, using 200μ fibers with low power and high emission period, laser light 980 is also used to first fill the edema and then increase the collagen matrix, in addition to 980 nm and micro The external use of the fibers of the micro lent point also reduces the freck line of each eyepiece in their first stage.

動物研究Animal research

18 Balb c小鼠被用於此研究。所選擇的小鼠被麻醉及一個小切口被施加於頸部區域。三個處理組被設定：在第一個處理組中，一塊5×5 mm、經mTHPC微脂粒調配物飽和之膠原蛋白被移植到皮膚之下。培育30分鐘之後，該區域以652nm、10J/cm2 的光線照射，在此之後，該區域以腸線及Hansaplast噴灑式熟石膏覆蓋。18 Balb c mice were used for this study. The selected mice were anesthetized and a small incision was applied to the neck area. Three treatment groups were set: in the first treatment group, a 5 x 5 mm collagen saturated with the mTHPC vesicle formulation was transplanted under the skin. After incubation for 30 minutes, the area was illuminated with light at 652 nm, 10 J/cm 2 , after which the area was covered with gut and Hansaplast sprayed plaster of Paris.

在第二組中，50 μl mTHPC微脂粒調配物被皮下注射及培育30分鐘，接著以652nm、10J/cm2 的光線照射，接著在皮膚之下藉由小切口開啟，移植未處理之膠原蛋白材料。在此之後，該區域被覆蓋及保護。In the second group, 50 μl of mTHPC liposome formulation was injected subcutaneously and incubated for 30 minutes, followed by irradiation with 650 nm, 10 J/cm 2 , followed by opening under a small incision under the skin, and transplanting untreated collagen. Protein material. After this, the area is covered and protected.

第三組係控制組，其中在小鼠中，傷口使用膠原蛋白及雷射照射處理(無mTHPC微脂粒調配物)。The third group is a control group in which the wound is treated with collagen and laser irradiation (no mTHPC liposome formulation).

使用於此處理之膠原蛋白產品包括Gentacoll、Kollagen Resorbs及膠原蛋白原纖維。在所有處理組中，每一組2隻小鼠被處理以這些膠原蛋白產品的每一種。Collagen products used in this treatment include Gentacoll, Kollagen Resorbs, and collagen fibrils. In each treatment group, 2 mice per group were treated with each of these collagen products.

經處理的小鼠係被保持觀察，以記錄傷口癒合中的進展。傷口癒合過程中的進展係在24小時、48小時、5及12天之後被紀錄。可注意在處理組2中，所有小鼠顯示非常好的反應且具輕微發炎及傷口係癒合良好；所有動物在該群組中皆存活的。而在處理組1中，小鼠在處理區域已經顯示強烈的紅色及發炎且毛髮缺失，但傷口癒合過程在12天期間係良好的，且在處理區域中具毛髮長回的情形。控制組3在開始處理的期間顯示非常強烈的發炎作用，具紅色及強烈腫脹。所有經膠原蛋白原纖維處理之小鼠顯示最佳的生物相容性(與其他所使用的膠原蛋白產品相比)。The treated mouse lines were kept under observation to record progression in wound healing. Progress in wound healing was recorded after 24 hours, 48 hours, 5 and 12 days. It can be noted that in treatment group 2, all mice showed very good response with mild inflammation and well wound healing; all animals survived in this cohort. While in treatment group 1, the mice had shown intense redness and inflammation and hair loss in the treated area, but the wound healing process was good during 12 days and had long hair back in the treated area. Control group 3 showed a very strong inflammatory effect during the start of treatment, with red and intense swelling. All collagen fibril treated mice showed the best biocompatibility (compared to other collagen products used).

圖1顯示對於三個群組以三種不同所使用之膠原蛋白產品，在14天之後，經處理小鼠之組織切片結果。當傷口以mTHPC微脂粒調配物被預處理時，加強的血管增生被觀察到。Figure 1 shows the results of tissue sectioning of treated mice after 14 days for the collagen products used in three different groups for three groups. Enhanced vascular proliferation was observed when the wound was pretreated with the mTHPC oligolipid formulation.

“本發明之進一步變化係用以治療動脈粥樣硬化性血管病。動脈粥樣硬化性血管病代表世界上主要健康問題之一；動脈粥樣硬化係動脈之不正常增厚及變硬，其造成係藉由脂肪酸堆積在血管之內層，形成粥樣的斑。在本發明中，光敏物被標靶於粥樣的斑，接著以適合波長的光能量照射，以在不正常增生平滑肌細胞引發細胞毒性效應，及在病灶控制微生物生長”。"Further variations of the present invention are for the treatment of atherosclerotic vascular disease. Atherosclerotic vascular disease represents one of the major health problems in the world; abnormal atherosclerotic arteries thicken and harden, The result is that atherosclerotic plaques are formed by fatty acid accumulating in the inner layer of blood vessels. In the present invention, the photosensitizer is targeted to atheroma-like plaques, and then irradiated with light energy of a suitable wavelength to abnormally proliferate smooth muscle cells. Initiates cytotoxic effects and controls microbial growth in lesions."

本發明係藉由以下例子被進一步闡明，但並不因此而受到限制。The present invention is further clarified by the following examples, but is not limited thereby.

實施例1Example 1 用於傷口癒合For wound healing

傷口區域用滅菌或食鹽水清洗及沖洗，用以移除細胞碎片、壞死及受傷害的細胞，及細胞分泌液及用以降低細菌感染。慢性傷口之清創需要被完成通常是因為非存活細胞及死亡細胞需要被移除，以防止細菌感染及促進肉芽組織形成，因而加速癒合過程。在傷口層以無菌溶液初次清洗之後，基於膠原蛋白之支撐基質係被施加到傷口層。在某些時間間隔之後，該部位係用適合波長被照射，以光活化光敏物。傷口層係保持無微生物感染，因而加快癒合過程。The wound area is washed and rinsed with sterile or saline to remove cell debris, necrotic and damaged cells, and cell exudates and to reduce bacterial infections. Debridement of chronic wounds needs to be completed usually because non-viable cells and dead cells need to be removed to prevent bacterial infection and promote granulation tissue formation, thus accelerating the healing process. After the wound layer is initially cleaned with a sterile solution, a collagen-based support matrix is applied to the wound layer. After some time interval, the site is illuminated with a suitable wavelength to photoactivate the photosensitizer. The wound layer remains free of microbial infections, thus accelerating the healing process.

實施例2Example 2 使用膠原蛋白材料及mTHPC微脂粒調配物以降低皺紋及疤痕Use collagen material and mTHPC oligosaccharide formulation to reduce wrinkles and scars

隨時間及曝露於環境因子下，皮膚開始老化，且皮膚中之膠原蛋白製造細胞(稱為纖維母細胞)逐漸降低數目。可見的效應係皮膚變薄及紋路與皺紋之出現。切適當的膠原蛋白海綿塊或取出所需數量之膠原蛋白原纖維，其以所需濃度(1.5ng/ml mTHPC)之mTHPC微脂粒調配物被飽和。該預處理之膠原蛋白材料係被置於一區域，其藉由外科手術刀的幫助在皮膚製造小切口被處理。培育30分鐘之後，該區域係以10J/cm2 (100mW/cm2 )光能量被照射。然後經PDT處理之區域係以外科敷料被覆蓋，膠原蛋白基質將促進細胞生長，因而矯正軟組織輪廓缺陷，例如皺紋及痤瘡疤痕。Over time and exposure to environmental factors, the skin begins to age, and collagen-producing cells (called fibroblasts) in the skin gradually decrease in number. Visible effects are thinning of the skin and the appearance of lines and wrinkles. Cut the appropriate collagen sponge pieces or remove the desired amount of collagen fibrils that are saturated with the mTHPC oligosaccharide formulation at the desired concentration (1.5 ng/ml mTHPC). The pretreated collagen material is placed in an area that is treated with a small incision in the skin with the aid of a surgical scalpel. After incubation for 30 minutes, the area was irradiated with light energy of 10 J/cm 2 (100 mW/cm 2 ). The PDT-treated area is then covered with a surgical dressing that will promote cell growth, thereby correcting soft tissue contour defects such as wrinkles and acne scars.

實施例3Example 3 處理牙周病Treatment of periodontal disease

在這個牙周病的個案中，被覆在牙齒的細菌(斑)攻擊支持牙齒於適當位置之物質：牙齒周圍之支撐組織已經被破壞，環繞根部的組織及環繞的骨骼已經被毀壞。此區域係以微脂粒調配之mTHPC及膠原蛋白基質處理；在培育時間之後，該區域以10J/cm2 光能量照射。新式膠原蛋白基質係被良好地接受及產生好的美容結果。在本發明中，PDT效果對於殺死該區域中齒齦下細菌也是有利的，因而加快該區域的癒合。In this case of periodontal disease, the bacteria (plaques) that are covered in the teeth attack the material that supports the teeth in place: the supporting tissue around the teeth has been destroyed, and the tissue surrounding the roots and the surrounding bones have been destroyed. This area was treated with micro-lipid-matched mTHPC and collagen matrix; after incubation time, the area was irradiated with 10 J/cm 2 of light energy. The new collagen matrix is well accepted and produces good cosmetic results. In the present invention, the PDT effect is also advantageous for killing bacteria under the gums in the area, thereby accelerating healing of the area.

實施例4Example 4 可注射形式之膠原蛋白當作真皮填充物Injectable form of collagen as a dermal filler

用於美容目的，用以移除疤痕、皺紋及其他皮膚瑕疵(特別在臉及頸部)：在此種個案中，Foslip被皮下注射進處理區域中，接著以電磁輻射照射及最後在皮膚下注射Zyplast以撫平皺紋。Zyplast(Inamed Aesthetics公司)係一種可注射膠原蛋白的形式，其與化學戊二醛連接，或Foslip預先與Zyplast混合而被納入。Used for cosmetic purposes to remove scars, wrinkles and other skin blemishes (especially on the face and neck): In this case, Foslip is injected subcutaneously into the treatment area, followed by electromagnetic radiation and finally under the skin. Inject Zyplast to smooth wrinkles. Zyplast (Inamed Aesthetics) is an injectable collagen form that is linked to chemical glutaraldehyde or that Foslip is previously mixed with Zyplast.

實施例5aExample 5a 骨骼及軟骨修復Bone and cartilage repair

骨骼及軟骨傷害也可以使用本發明被處理，基於膠原蛋白的材料(像是Chondro－Gide 、Chondrocell)可以與微脂粒調配之mTHPC及PDT共同被使用，以幫助被磨損或被破壞的軟骨及骨骼生長。Bone and cartilage injuries can also be treated with the present invention, based on collagen-based materials (like Chondro-Gide) Chondrocell It can be used together with mTHPC and PDT formulated with liposome to help the cartilage and bones that are worn or destroyed to grow.

實施例5bExample 5b 後PDT光調節Post PDT light adjustment

在本發明之另一個具體實例中，980nm雷射光係在後PDT時期被使用在處理區域，用以光調節。細胞活性係使用光源被調整。In another embodiment of the invention, a 980 nm laser light system is used in the processing region during the post-PDT period for light conditioning. Cellular activity is adjusted using a light source.

實施例6Example 6 使用脂肪組織當作基質Use adipose tissue as a matrix

首先，脂肪組織從giber區域被吸取及在被附加到Foslip之後(最終組織濃度在1.5到3 ng/g脂肪移植組織之間)，準備用以移植到溝或軟組織畸形，然後準備好填充該區域及最後在24小時中make tea光活化。它係自體脂肪注射法。一部份脂肪組織表現當作移植物及其餘的被破壞，及像膠原蛋白一樣被納入處理區域中。PDT作用幫助良好的膠原蛋白基質納入，其基本上係藉由維持額外的細胞基質平衡，因而增進新的膠原蛋白形成。First, adipose tissue is drawn from the giber area and after being attached to the Foslip (final tissue concentration between 1.5 and 3 ng/g of fat graft tissue), ready to be transplanted into a furrow or soft tissue deformity, then ready to fill the area And finally, make tea light activation in 24 hours. It is an autologous fat injection method. A portion of the adipose tissue appears to be destroyed as a graft and the rest, and is incorporated into the treated area like collagen. The PDT action aids in the incorporation of a good collagen matrix, which essentially promotes new collagen formation by maintaining an additional cell matrix balance.

本發明並非只限制在其應用於特定於以上實施例中之例子，而且也包括牙科應用，心血管、傷口癒合及美容應用。一種牙科應用係牙周囊袋之處理。The invention is not limited only to its application to the examples specific to the above examples, but also includes dental applications, cardiovascular, wound healing and cosmetic applications. A dental application is the treatment of a periodontal pocket.

已經描述本發明之較佳實施例(參見所附之圖式)，要瞭解的是，本發明並不限制於精確的實施例，及許多改變及調整可以在此藉由那些熟於此技藝的人被實現，而無違反本發明如定義於所附申請專利範圍中之範圍或精神。The preferred embodiments of the present invention have been described (see the accompanying drawings), and it is understood that the invention is not limited to the precise embodiments, and many variations and modifications may be made by those skilled in the art. A person is realized without departing from the scope or spirit of the invention as defined in the appended claims.

圖1顯示在小鼠處理14天後之組織切片結果。Figure 1 shows the results of tissue sectioning after 14 days of treatment in mice.

圖2係在雷射照射期間，膠原蛋白熱穩定性之巨觀圖片。Figure 2 is a macroscopic picture of the thermal stability of collagen during laser irradiation.

圖3係在顯微鏡程度下，當曝露於不同能量水平時，膠原蛋白之熱穩定性。Figure 3 is the thermal stability of collagen when exposed to different energy levels at the microscope level.

Claims (7)

一種用於組織重新形成(reformation)、組織增大或二者之醫藥套組，其特徵在於該套組包括複數個容器，其中至少一個該容器包括至少一種包含mTHPC(替莫泊芬(temoporfin))的光敏物化合物，且其中至少一個其他的該複數個容器包括至少一種選自由水凝膠、聚合物、糖蛋白、膠原蛋白、脂肪、非動物性穩定型透明質酸、多醣、多胜肽、及這些材料之組合所組成之群組的生物可相容基質材料。 A medical kit for tissue reformation, tissue augmentation or both, characterized in that the kit comprises a plurality of containers, at least one of which comprises at least one comprising mTHPC (temoporfin) a photosensitizer compound, and wherein at least one other of the plurality of containers comprises at least one selected from the group consisting of hydrogels, polymers, glycoproteins, collagen, fats, non-animal stable hyaluronic acid, polysaccharides, polypeptides And a biocompatible matrix material of the group consisting of these materials. 根據申請專利範圍第1項之醫藥套組，其進一步包括至少一個容器，其包括至少一種選自由上皮生長因子、血小板衍生的生長因子、組織血管新生生長因子、細胞介素、角質細胞、上皮細胞及纖維母細胞所組成群組之細胞成分。 The medical kit of claim 1, further comprising at least one container comprising at least one selected from the group consisting of epithelial growth factors, platelet-derived growth factors, tissue angiogenic growth factors, interleukins, keratinocytes, epithelial cells And the cellular components of the group composed of fibroblasts. 一種用於組織再生及傷口癒合之生物可相容組成物，其包括至少一種生物可相容基質材料，其中該材料係選自由水凝膠、聚合物、糖蛋白、膠原蛋白、脂肪、非動物性穩定型透明質酸、多醣、多胜肽、及這些材料之組合所組成的群組；及包含mTHPC(替莫泊芬)的光敏物化合物。 A biocompatible composition for tissue regeneration and wound healing comprising at least one biocompatible matrix material, wherein the material is selected from the group consisting of hydrogels, polymers, glycoproteins, collagen, fats, non-animals a group consisting of a stable hyaluronic acid, a polysaccharide, a multi-peptide, and a combination of these materials; and a photosensitizer compound comprising mTHPC (Temoprofen). 根據申請專利範圍第3項之組成物，其特徵在於該組成物進一步包括至少一種選自由上皮生長因子、血小板衍生的生長因子、組織血管新生生長因子、細胞介素、角質細胞、上皮細胞及纖維母細胞所組成群組之細胞成分。 The composition according to claim 3, characterized in that the composition further comprises at least one selected from the group consisting of epithelial growth factors, platelet-derived growth factors, tissue angiogenic growth factors, interleukins, keratinocytes, epithelial cells and fibers. The cellular component of a group of mother cells. 一種包括至少一種生物可相容基質材料與mTHPC (替莫泊芬)的生物可相容組成物的用途，其係用於製備用於治療組織重新形成及/或增大的醫藥品，該治療包括投予具有該光敏物及該生物可相容基質的醫藥品，以及以波長可被該光敏物吸收到該治療區域之電磁輻射活化該裝載光敏物之基質。 One comprising at least one biocompatible matrix material and mTHPC Use of a biocompatible composition of (tenpherone) for the preparation of a medicament for treating tissue re-formation and/or augmentation, the treatment comprising administering the photoactive substance and the biocompatible phase The medicinal material of the matrix, and the electromagnetic radiation having a wavelength that can be absorbed by the photosensitive material into the treatment region, activates the substrate on which the photosensitive material is loaded. 根據申請專利範圍第5項之用途，其特徵在於該生物可相容基質材料係包括選自由水凝膠、聚合物、糖蛋白、膠原蛋白、脂肪、非動物性穩定型透明質酸、多醣、多胜肽，及這些材料之組合所組成群組之生物可分解材料。 The use according to item 5 of the patent application, characterized in that the biocompatible matrix material comprises a material selected from the group consisting of hydrogels, polymers, glycoproteins, collagen, fats, non-animal stable hyaluronic acid, polysaccharides, A biodegradable material consisting of a multi-peptide, and a combination of these materials. 根據申請專利範圍第6項之用途，其特徵在於該光敏物進一步包括mTHPC(替莫泊芬)的微脂粒載體調配物。 Use according to item 6 of the patent application, characterized in that the photosensitizer further comprises a liposome carrier formulation of mTHPC (Temoprofen).
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